Spontaneous bleeding in COVID-19: A retrospective experience of an Italian COVID-19 hospital

Background Haemorrhages in coronavirus disease 2019 (COVID-19) patients require proper knowledge and management. Objectives To highlight the characteristics of haemorrhages in patients with COVID-19 infection. Method A retrospective study examined CT scans performed over a 13-month period in patients hospitalised with COVID-19 infection to determine those who developed spontaneous bleeding. The authors also investigated correlations between the bleeding events and the patients’ characteristics. Results Haemorrhages occurred in 2.22% (31/1396) of patients hospitalised with COVID-19 infection (7.88%, 19/241 in the intensive care unit). Bleeding, major in most cases, occurred in anticoagulated patients, especially males with multiple comorbidities, aged between 60 and 79 years and mainly appeared in a single anatomical region (especially retroperitoneal), with the most voluminous in the chest wall. The complication was diagnosed on average 16.7 days after admission and occurred predominantly in critically ill patients undergoing invasive ventilation and pronation-supination cycles. In just under half of the cases, the haematomas were active, and in these cases, mainly with a single contrast blush and with earlier onset after the start of anticoagulation than in non-active bleeding. Major bleeding was also earlier in the presence of multiple morbidity. The vast majority of patients were treated conservatively and survived. Conclusion At COVID-19 hospital centres, it is advisable that there is knowledge of such a complication for which CT imaging is essential for diagnosis and proper management. Although some authors have expressed doubts about anticoagulant treatment in patients with COVID-19, the bleeding complication in this study did not significantly affect the outcome. Contribution Spontaneous haemorrhage did not significantly affect the outcome in this series.


Introduction
Haemorrhagic complications in coronavirus disease 2019 (COVID-19) patients require management referral from spoke facilities and biocontainment measures to central facilities (hub). 1 CT imaging plays a pivotal role in the management of COVID-19 infection, particularly in critically ill patients. Since the onset of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, CT has been the dominant modality in defining the severity of pulmonary involvement by allowing a rapid and preliminary stratification of patients into risk categories, providing useful elements for therapeutic planning and prognostic evaluation. CT imaging also has a fundamental role in the diagnosis and monitoring of complications, most of which are life-threatening, such as neurological, vascular, gastrointestinal or renal complications, thus improving the outcome of COVID-19 patients. 2,3

Materials and methods
This was a single-centre retrospective observational study. The Radiology Information System-Picture Archiving and Communication System (RIS-PACS) database was analysed by examining all the CT scans performed from 01 March 2020 to 30 April 2021 in patients hospitalised with COVID-19 infection at 'M. Magalini' Hospital, Villafranca di Verona -AULSS 9 Scaligera, Verona, Veneto, Italy.
Male and female patients affected by COVID-19 (confirmed with molecular research of viral DNA using a nasopharyngeal swab) and who developed one or more haematomas during hospitalisation, were included. The CT examinations performed in both the unenhanced and post-contrast phases, involving at least one of the following body areas, were included in the evaluation: neck, thorax, abdomen, upper and lower limbs and pelvis. Any examinations targeting the spine, skull, and facial bones as well as those performed on patients with pathologies other than COVID-19 were excluded.

Imaging, clinical, laboratory and therapeutic aspects
All studies were performed with a 16-layer multidetector CT scanner (TOSHIBA Astelion 16, Japan), 120 kV. The acquisition protocols involved an unenhanced phase, and when completed with intravenous iodenated contrast administration (iopromide, Ultravist 370 mg/mL, 1.2 mg/ kg, Bayer HealthCare Pharmaceuticals Inc., Berlin, Germany), they were performed with bolus tracking, using an infusion flow of not less than 3.5 mL/s, with arterial (15-20 s), venous (60-70 s) and sometimes late (3-5 min) phase scans. The images were transmitted to the PACS for post-processing. Multiplanar reconstruction (MPR) and reprocessing was carried out with IMPAX Client software version 6.6.1.0 (AGFA HealthCare NV, Mortsel, Belgium).
Data recorded included whether the detected haematomas were single or multiple, noting the specific anatomical structures where the bleeding was located and grouping them into the following locations: thoracic wall, thoracic cavity, abdominal wall, retroperitoneum, intraperitoneal, pelvis, neck, upper and lower limbs. For each haematoma, the latero-lateral, craniocaudal and anteroposterior diameters were measured by means of MPR reconstructions, expressed in centimetres, approximating the measurements to the nearest whole number. The shape of the haematomas was qualitatively evaluated equivalent to ellipsoids, estimating their volume in cubic cm = mL with the formula: using the online tool https://keisan.casio.com/exec/ system/1223392149. For each haematoma, the presence of contrast blush, uni-or multifocal, in the arterial and venous phase was investigated.
Additional data included patient age and sex, hospitalisation date, discharge date, start of anticoagulant treatment date, length of hospitalisation, date of the first CT examination diagnostic for haematoma and number of days elapsed between this examination and the date of hospitalisation and initiation of anticoagulation, and whether during the hospitalisation they were admitted to the intensive care unit (ICU). These patients were standardised to receive enoxaparin twice a day (bid) based on body weight: 4000 U bid if < 80 kg, 6000 U bid if between 80 kg and 120 kg, 8000 U bid if > 120 kg. The enoxaparin dosage was modulated in relation to the D-dimer trend, creatinine clearance (< 30 mL/min), occurrence of bleeding and anaemia. All ICU patients who developed haematomas were transfused with at least one bag of concentrated red blood cells to ensure adequate oxygen delivery.
In relation to the haemodynamic stability/instability and the blood count trend, a conservative approach was implemented with remodelling of the anticoagulant therapy using calcium heparin suspension of anti-aggregation and transfusion of multiple bags of red blood cells. If invasive management was necessary, the patients were transferred to the reference hub.
The data of patients who underwent invasive mechanical ventilation, reported trauma and major bleeding during hospitalisation, defined according to the criteria of the International Society on Thrombosis and Haemostasis (ISTH), were recorded. 4 For each patient, previous comorbidities, any anticoagulant or antiplatelet treatments in place at the time of admission and some laboratory parameters measured at the time of both admission and the first diagnostic CT study were deduced from the electronic medical records. The appearance of other relevant complications, particularly of a thromboembolic ischaemic nature, diagnosed by CT, was also investigated. Finally, the outcome in patients discharged and deceased (from any cause) was recorded.

Statistical analysis
The study utilised the IBM ® SPSS ® Statistics software package, version 28.0 (IBM Corp., Armonk, NY, United States [US]).

Imaging
Haematomas were diagnosed on contrast CT scans in 30/31 cases (96.78%) while in 1/31 cases (3.22%) the diagnosis was reached by unenhanced CT imaging in a patient with reduced glomerular filtration rate; given the haemodynamic stability, a contrast medium injection was not necessary for the investigation.
The first CT diagnosis of haematoma was made on average at 16.70 days from hospitalisation (range 0-33 days), at 18.7 days in ICU patients (range 5-33) and at 13.6 days in patients admitted to other units (range 0-31 days). The diagnosis was made at admission in two patients.
In all cases, unenhanced CT images revealed the presence of volumetric increase of the anatomical structures involved, which were inhomogeneously hyperdense (~ 60 Hounsfield Units). None of the cases raised differential diagnostic doubts with other pathologies (e.g. abscesses or sarcomas), given the clinical history (e.g. anaemia, hypotension, anticoagulant treatment) and imaging characteristics (e.g. absence of gas within the lesions, absence of calcifications or contrast enhancement, presence of contrast medium spillage) (Figures 1-8).
In 3/31 cases (9.67%) there was a history of trauma: two cases of accidental falls with minor injury and with an unclear correlation with bleeding diagnosed after a few days (retroperitoneal haematoma of 1900 mL, haematoma of 824 mL of the rectus femoris muscle), while in the third case, a small haematoma developed adjacent to the access site of a jugular central venous catheter. Iatrogenic significance was attributed to this bleeding (p = 0.001; r = 0.56), however, a retroperitoneal haematoma developed the next day without any trauma correlation. In 22/31 patients (70.96%) the haematomas were single, while in 9/31 patients (29.04%), multiple haematomas were found with a total of 43 anatomical sites affected, listed in Table 1. There was a significant correlation between the presence of bleeding in the retroperitoneal space (p = 0.019; r = 0.42) and in the pelvis (p = 0.022; r = 0.41) and the development of multiple haematomas.
In 46.66% CT exams (14/30 performed with contrast medium), the authors found active arterial contrast extravasation (Table  1) A correlation was found between active haematomas and a  unifocal blush (p = 0.000; r = 0.65) and with multifocal contrast extravasations (p = 0.002; r = 0.54). Significant correlations were observed between the presence of active arterial blush and male sex (p = 0.031; r = 0.39) and between the same event and a history of antiplatelet therapy for previous comorbidities (p = 0.022; r = 0.41). Finally, a significant inverse correlation was observed between bleeding with active contrast extravasation and the time elapsed from the start of anticoagulant treatment (p = 0.03; r = −0.43); haematomas with active bleeding occurred earlier.

Laboratory
Result averages at admission and at CT diagnosis are listed in Table 2. There was a significant inverse correlation between major bleeding and haemoglobinaemia at the time of diagnosis (p = 0.004; r = −0.51), while a significant inverse correlation was found between platelet blood count at the time of diagnosis and the development of multiple haematomas (p = 0.027; r = −0.39). A significant inverse correlation was observed between the development of active bleeding and the activated partial thromboplastin time (aPTT) ratio on the day of hospitalisation (p = 0.05; r = −0.36).

Comorbidities
The presence and/or absence of comorbidities is listed in Table 2. The authors found a significant direct correlation between the presence of multiple comorbidities and arterial hypertension (p = 0.002; r = 0.52), while obesity was more significant in males (p = 0.018; r = 0.42). The inverse correlations between age and obesity (p = 0.000; r = −0.69) and age and type II diabetes (p = 0.01; r = −0.45) were very significant. A significant inverse correlation between the presence of multiple comorbidities and the time elapsed from hospitalisation to diagnosis (p = 0.046; r = −0.36) was also observed; in these patients, the haematomas developed earlier.

Other complications
Of the 31 patients, 10 (32.25%) developed thromboembolic ischaemic complications during hospitalisation despite all being anticoagulated patients; 7/31 patients (22.58%) developed pubmonary thromboembolism (PTE) (Figures 3  and 6), in one case with deep vein thrombosis (DVT) (Figure 6), one subtotal splenic infarction (Figure 1), one subtotal renal ischaemia and one DVT. In 25/31 cases (80.65%) the treatment of haematomas was conservative, while 6/31 patients (19.35%) underwent endovascular embolisation at the hub hospital; 2/6 (33.3%) later demised. The haematomas were not surgically evacuated in any of the cases. A significant direct correlation was found between embolisation and active contrast extravasation (p = 0.002; r = 0.54) and with the evidence of multifocal contrast blushes on CT (p = 0.001; r = 0.59). The main imaging and population characteristics are summarised in Table 1 and Table 2.

Role of anticoagulation in COVID-19 therapy and risk factors for haematomas
Anticoagulant treatment is recognised as a possible cause of muscle haematomas in adult patients unaffected by 6 During the COVID-19 pandemic, in addition to the pulmonary and neurological manifestations, the alteration of the coagulation pathway soon appeared significant, which represented the rationale for the use of heparin. 5,7,8,9,10,11,12,13,14,15,16 This alteration resulted both in the form of hypercoagulability 11,14,17 with expressions of a thromboembolic nature (e.g. PTE, DVT), whose mechanism is still necessary to investigate, 13 and in the form of haemorrhagic diathesis with depletion of coagulation factors, thrombocytopenia and hyperfibrinolysis. 14,18 Among the risk factors for the development of bleeding in COVID-19 patients, contributing causes have been proposed, such as pronation manoeuvres, anticoagulant treatment, obesity, increased vascular fragility determined by the proinflammatory state, barotrauma from ventilation by C-PAP and cough with consequent increase in intra-abdominal pressure and arterial rupture. 17,19 Many of these risk factors coincide with those that have been documented in this article.
Godier and colleagues observed that bleeding occurred in the hyperinflammation reduction phase typical of these patients, as evidenced by the reduction of fibrinogen and D-dimer. 20 The biphasic coagulative alterations proposed by them, firstly pro-thrombotic and subsequently haemorrhagic in the phase of resolution of the inflammation, could be useful in explaining the average 16.7 days which elapsed from hospitalisation to diagnosis in our population. Other authors have also highlighted the development of the complication at about two weeks. 21,22 As proposed by Kessler et al., it could therefore be reasonable to reduce anticoagulant treatment after 10-14 days in patients with favourable clinical progress. 23

Epidemiology
Qiu et al. reported that COVID-19 itself represents a risk factor for bleeding by detecting bleeding in 35% of a cohort of these patients versus 10% in a cohort of patients with community-acquired pneumonia. 24 A frequency of bleeding complications ranging from 4.8% to 8% with 3.5% major bleeding has been reported in patients with COVID-19. 9,25,26 However, these frequencies are widely variable. Fraissé et al. reported a bleeding rate of 21% in their critically ill patients, 84% after anticoagulation at therapeutic doses. 27 In two different papers, Al-Samkari et al. reported an overall bleeding rate of 4.8% with 2.3% major bleeding 9 while in critically ill patients they reported a 2.8% rate of major bleeding approximately two weeks after admission to the hospital ICU. 28 Demelo-Rodriguez et al. found less frequent bleeding in patients admitted to the non-intensive ward compared with those in intensive care. 29 In our case study 61.29% of bleeding (19/31) occurred in ICU patients compared with 38.71% (12/31) in patients in other wards, although this difference did not show significance.
Lucatelli et al. 1 reported a predominance of this complication in males (68.00% vs 74.20% in this study) and multifocal bleeding in 68.40% of cases, which is higher than the 29.03% in this study. In the authors' ICU, the incidence of complication was 7.88% (19/241) with 7.46% (18/241) major bleeding, compared with an overall incidence of 2.22% (31/1396) with 2.07% (29/1396) major bleeding; the data are substantially comparable to that reported by other authors. 30,31 Symptoms and imaging Muscular haematomas are blood spills in a muscle group that can remain contained by the fascial plane or spread to adjacent spaces (e.g. peritoneum) and are spontaneous if not associated with trauma. 32 Symptoms of muscle haematomas are of variable magnitude: local (e.g. skin hypersensitivity, peritoneal signs in the abdominal wall or retroperitoneal haematomas) and general (e.g. tachycardia, hypotension, pallor), while complications include compartment syndrome, superinfections, compressive neuropathies and diffusion in adjacent spaces (e.g. haemoperitoneum). 32,33 CT imaging with contrast medium is the gold standard for diagnosis and allows for defining the topography and size of the bleeding, highlighting compression complications, showing active contrast extravasation, providing useful indications to the interventionist on the bleeding vessel, as well as evaluating the possible coexistence of thromboembolic or ischaemic manifestations. 8,13,26,32,34 Dohan and colleagues argued that the presence of active bleeding is related to a greater severity of the clinical picture. 32 38 Lucatelli and colleagues highlighted the role of COVID-19induced thrombocytopenia as a cause for an increased risk of major bleeding during treatment with therapeutic dose heparin. 1 In the work of Al-Samkari et al., the D-dimer value at hospitalisation was considered predictive of the risk of bleeding, thrombosis, clinical severity and death while the prolongation of the prothrombin time was associated with a reduction in survival and a worse clinical picture. 9 In this case study, although the mean INR, aPTT and blood platelet count values were normal at the time of haematoma diagnosis, more active bleeding was observed in patients with lower aPTT values at admission and multiple bleeding in patients with lower blood platelet count values at diagnosis. The mean D-dimer value was high both at admission and at diagnosis, although this was not statistically significant. Patients with a poor outcome had lower haemoglobin on admission.

Treatment
As there are no guidelines for the treatment of the complication, treatment must be multidisciplinary and 'tailored' to the individual patient. 11,13,39 However, Lucatelli et al. supported the endovascular approach compared to conservative management. 18 Riu and colleagues highlighted some severity criteria such as active blood extravasation, retroperitoneal site, conspicuous size, haematoma wall rupture, reduction in haemoglobin greater than 2 g/dL or 3 g/dL, need for repeated transfusions and presence of thromboembolic complications with difficulty in interrupting anticoagulation. 39 Dohan and colleagues proposed the surgical option in cases of nerve compression or cutaneous ischaemia, however, highlighting frequent relapse with this approach. They underlined that small intrafascial haematomas can selfresolve, suggesting an endovascular approach for voluminous active haematomas. 32 Interestingly, while highlighting how heparin-induced bleeding tends to self-resolve upon discontinuation of anticoagulant treatment, Lucatelli et al. decided not to discontinue this therapy, considering it necessary in patients with COVID-19, given its association with an increase in survival in critically ill patients. 1,40,41,42 In this case study, 80.65% of patients (25/31) were managed conservatively. Among the six embolised patients, two died (33.33%) versus two (8.00%) patients who died among the 25 patients managed conservatively; however, this difference was not statistically significant.

Outcome
Mattioli et al. believed that the risk of haemorrhagic events could be underestimated as the focus appears more on the pro-thrombotic side of the alterations in the coagulative cascade, possibly also because of the lower lethality of the haemorrhagic complications. 14

Conclusion
Although some authors have expressed doubts about anticoagulant treatment in patients with COVID-19, 43,44,45 the bleeding complication in this study did not significantly affect the outcome. Bleeding, major in most cases, occurred in anticoagulated patients, especially males with multiple comorbidities (e.g. obesity and heart disease), aged between 60 and 79 years and mainly appeared in a single anatomical region (especially retroperitoneal), with the most voluminous in the chest wall. The complication was diagnosed on average 16.7 days after admission and occurred predominantly in critically ill patients undergoing invasive ventilation and pronation-supination cycles. In just under half of the cases, the haematomas were active and mainly with single contrast extravasation. In addition, taking into account the start of anticoagulation, haematomas with active bleeding had an earlier onset than those without contrast blush. Major bleeding was also experienced earlier in the presence of multiple morbidity and the vast majority of patients were treated conservatively and survived.
At COVID-19 hospital centres, it is advisable that there is knowledge of such a complication for which CT imaging is essential for proper management.

Limitations and bias
The study is retrospective in nature and in the absence of a control group it is difficult to state the real impact of the complication on the outcome. Anticoagulant treatment is another bias; moreover the authors did not stratify the population based on the dose of anticoagulant administered. In patients who developed multiple haematomas, we only reported the date of the first diagnostic CT scan and only bleeding diagnosed by CT was recorded. The history of non-iatrogenic trauma found in two patients could be a confounding factor.